Preparation of o-hydroxy aldehydes by oxidation of substituted phenols



Patented Apr. 29, 1954 UNITED STATES ATENT OFFICE PREPARATION OFo-HYDROXY ALDEHYDES BY OXIDATION OF SUBSTITUTED PHE- NOLS ware

No Drawing. Application October 20, 1949, Serial No. 122,578

a Claims.

This invention relates to the production of hydroxy aldehydes, and, moreparticularly, to a method for oxidizing o-hydroxy benzyl alcohols toproduce the corresponding o-hydroxy aldehydes.

It has been known that saligenin (o-hydroxy benzyl alcohol) can beoxidized to produce salicylaldehyde and salicylic acid. For example,Piria, Liebigs Annalen der Chimie, vol. 56, pages 42-43 (1845), andTrillat, Bulletin de la Societe Chimique, Third Series, vol. 29, page 45(1903) disclose the oxidation of saligenin in the presence of platinumblack, and Trillat states that saligenin is oxidized to salicylaldehydein the presence of a platinum spiral. However, saligenin and itsderivatives are readily oxidized to the acid; it is extremely difficultto conduct the oxidation in such a way that only the aldehyde isproduced, and methods heretofore known for conducting such oxidationhave resulted in comparatively low yields of the desired aldehydes. Forexample, saligenin has been oxidized by oxygen in the presence ofplatinum black, but it has not been found to be possible to convert morethan five per cent of the saligenin to salicylaldehyde by this method.This oxidation has also been carried out (in air, in an oxygenatmosphere, under pressure; and in the absence of oxygen, as adehydrogenation) in the presence of other catalysts (e. g., osmium,platinum oxide, platinum on zirconium oxide and platinum on pumice), butin no case has it been found to be possible to convert more than fifteenper cent of the saligenin to salicylaldehyde. The present invention isbased upon the discovery of a new way for oxidizing saligenin or asubstituted saligenin to the corresponding hydroxy aldehyde; thepreferred embodiments of the new method can be used to effect asubstantially greater yield of the desired aldehyde than has beenachieved by the known method.

The principal object of the invention is to provide an improved methodfor producing salicylaldehyde or a substituted salicylaldehyde fromsaligenin or a substituted saligenin. More specific objects andadvantages are apparent from the description which illustrates anddiscloses but does not limit the invention.

In accordance with the invention an o-hydroxy aldehyde is produced fromsaligenin or a substituted saligenin. Saligenin and substitutedsaligenins are hereinafter for convenience called substituted phenols.The substituted phenols that are used have one ortho substituent of theformula -CH2OH, any other substituent being a halo, alkyl or alkoxygroup. The substituted phenol is treated with a lower alkoxide ofaluminum to form an aluminum derivative of the substituted phenol. Thealuminum derivative is then oxidized by the action of acarbonyl-containing compound, and the pH of the resulting mixture isadjusted to convert the aluminum salt to the hydroxy aldehyde.

Although the invention is not limited to the theoretical explanationthat follows, it is believed that the following reactions occur when theprocess of the invention is used to convert saligenin tosalicylaldehyde:

, (a) An aluminum derivative is formed by reaction between the saligeninand the lower alkoxide of aluminum; both the hydroxyls of saligenin formaluminum derivatives but each alu- ,minum atom may react so that it islinked Al-O CHr-O-Al-O-HzC- 4HOR in which R represents an alkyl radical.

(b) The desired oxidation is effected by the action of acarbonyl-containingcompound on the aluminum derivative. This reaction isillustrated by Equation 4, below, which shows acetone as thecarbonyl-containing compound.

(c) 'The desired o-hydroxy aldehyde is pro- 'duced from the aluminumsalt of the hydroxy aldehyde (shown as a product of Equation 4) by theaction of an aqueous acid or by the action of an aqueous base followedby an aqueous acid.

As is illustrated by Equation l, a dynamic equilibrium condition isapproached when a substituted phenol and a carbonyl-containing compoundare reacted. It is usually desirable that the reaction proceedsubstantially to the equilibrium condition; in this way approximatelythe maximum yield of product is achieved with a minimum of recycling.However, it is feasible to stop the reaction before equilibrium isreached and thereby shorten the reaction :time. When reaction hasproceeded to the desired extent, an aqueous acid or an aqueous base isadded to the mixture to destroy the aluminum derivative andtherebytoprevent further reaction in either direction. Equilibrium isachieved, under gentle reflux at atmosphericpressure, Withinabout tenhours. Ordinarily there is no reason to maintain the reaction mixtureunder reflux after equilibrium is achieved,but the y-i'eldof product isnot affected by so continuing. Usually it is desirable that the reactionmixture be refluxed for at least about four hours and preferred that itbe refluxed for at least about six hours. Ordinarily, conducting thereaction of the invention at pressures other than'atmospheric cannot bejustified economically, so the maxi'num practical temperature is thereflux temperature at atmospheric pressure. ,It is, accordingly, usuallydesirable to conduct the reaction at about this temperature.

In general, as is hereinbefore stated, the method .ofthe invention isused to convert saligenin or a substituted saligenin to salicylaldehydeor a substituted salicylaldehyde. Although the method can sometimes beused when the saligenin has other substituents, it is usually pre ferredthat the startingmaterial be saligenin or a halo-, alkyl-,or-alkoxy-substituted saligenin.

m bon atoms) vention involves the use of a fiuoro saligenin, mostdesirably 3-fluoro saligenin:

ticularly 3-fiuoro1salicylaldehyde:

i -F 41H which result when this starting material is usedhave'particular utility in the production of oxygen-carrying chelates(see J. Am. Chem. Soc, vol. 68, p.'.2254 ettseqJi The halosubstituentscan beffiuoro, chloro, bromo,oor iodo. The alkyl substituent,:or:thealkylpart of the alkoxy substituent, canbe *primarygsecondary, ortertiary; the number of carbon atoms is limited only by prac .ticalconsiderationswvhich:usually make it desirable that the alkyl or alkoxyradicalshave not more'than about sixteen carbon'atoms.

As has been'indicated, anialuminum derivative of a substitutedphenolis-produced by treatingthe substituted phenol with an aluminum alkoxide.:Ingeneral, the rate at which such derivatives are formed from analuminum alkoxide .is an inverse function of the molecular weight of thealkoxy group thereof. Accordingly, it is usually desirable that thealuminum allioxide used beone in which the alkoxy radical is a loweralkoxy radical (i. e.,*has"notxmore than five car- Asisiindicated byEquations 1, 2 and 3, above, the alkoxyradical oi the aluminum :alkoxideis'converte'd to the corresponding alcoholin-theicourse.of'theiformation of the aluminum'qderivative :of the substitutedphenol. "Primary and secondary: alcohols undergo oxidation zreactionssimi'lar to "that undergone by a substituted phenol iin'accordance withthe invention. ;-According'ly,iif the aluminum alkoxide usedis onehaving aiprimary'or secondary alkoxy :radical, the :alcohol producedtherefrom shouldpbecompletely separated from the reaction "mixture*before the carbony1containing com- DOIIIld'I'lS added ithereto..iBecause tertiary alcoholsdo notundergosuch an oxidation there isj'noneed'to remove tertiaryalcohols so produced from tertiaryalkoxyradicals, and the use .of aluminum :a-lkoxides comprising tertiaryalkoxy 'radicalsris aipreferred embodiment of the invention. Aluminumtertiary butoxideis'the most advantageous material :for :such usebecause it isthe most readily: available and least expensive of thosethat yield tertiary. alcohols. :Ordinarily .itis?desirableithatithei'molar' ratio'of the lower aluminum alkoxide. tosubstituted phenol be from :aboutfiifi'? gtosabout;3.iandpreferable-that it be :from about :litor. about 22.

in ':general, :any carbonyl-containing organic compound'(i.re.,:any:ketone or aldehyde) can be used to.;convert:the'aluminumderivative of a substitutedtphenol to 'the aluminum salt of thecorresponding :hydroxy aldehyde. This is true Lbecause ;the :carbonyllrgroup, is .the' part of :the tmoleculeseifective carrying llOlltftheldesired -oxidation andgslibstituents thatzarei usual1y;pres- .entwith-rcarbonyl ;groups-do;not interfere with A particularly desirableembodiment of the in- .the :oxidation. For :exampla isuch vastly :dif-

stal

in which R is hydrogen, or an alkyl, aralkyl, alkenyl, alkynyl, aryl orallraryl radical. When R is anything other than hydrogen, the radicalrepresented by R can be substituted with a halo or an alkoxy radical. Ris alkyl, aralkyl, alkenyl, alkynyl, aryl or alkaryl. R. can besubstituted with a halo or an alkoxy radical. It is usually desirablethat the total number of carbon atoms in each of the radicals R and R benot more than twenty, and that there be not more than four halosubstituents in either of these radicals. The halo substituent may befiuoro, chloro, bronio or iodo. Apparently, aldehydes are less stable,under the conditions used in the practice of the invention, than areketones; for this reason aldehydes are more active oxidizing agents foruse in the practice of the invention than are ketones. Because aldehydesare more active, the dynamic equilibrium illustrated by Equation 4,above proceeds farther (i. e., converts a larger percentage of thealuminum derivative of the substituted phenol to the aluminum salt ofthe hydroxy aldeyhde) when an aldehyde rather than a ketone is theoxidizing agent. For this reason aldehydes are preferredcarbonyl-containing compounds for use in the practice of the invention.The reaction is usually conducted under gentle reflux at atmosphericpressure, and it is desirable to use a substantial excess (e. g., fromabout to about 100 mols of the carbonyl-containing compound, andpreferably from about to about mols thereof, per mol of the substitutedphenol charged) of the carbonyl-containing compound to drive theequilibrium represented by Equation 4, above, in the desired direction.Therefore, it is usually advantageous to use a relatively high boilingcarbonyl-containing compound. Accordingly, aromatic aldehydes, beinghigh boiling compounds, and being members of the active class ofcarbonyl-containing compounds (i. e., aldehydes) are particularlydesirable carbon-containing compounds for use in the practice of theinvention. It is usually desirable that the aromatic aldehyde have fromone to two benzene nuclei, any substituents attached thereto beingalkyl, alkoxy, or halo radicals. It is advantageous that no alkyl oralkoxy radical have more than six carbon atoms, and that the totalnumber of carbon atoms in the aromatic aldehyde be not more than twenty.O-chlorobenzaldehyde is an example of this preferred class ofcarbonyl-containing compounds.

As is indicated by Equation 4, above, an aluminum salt of the desiredhydroxy aldehyde is produced by means of the reaction between thecarbonyl-containing compound and the substituted phenol. This aluminumsalt is convenient 1y converted to the desired ortho-hydroxy aldehyde by(a) adding an aqueous acid to the reaction mixture or (1)) adding anaqueous base 6, thereto and acidifying the salt formed. The organicmaterial is then conveniently separated from the reaction mixture by asteam distillation or by solvent extraction. Since the desired oxidationreaction proceeds only between an aluminum derivative of a substitutedphenol and a carbonyl-containing compound, the reaction is stopped byadding an aqueous acid or an aqueous base to the reaction mixture.

The following examples illustrate the new process, but are not to beconstrued as limiting the scope of the invention.

Example 1 An o-hydroxy aldehyde was produced from a substituted phenolaccording to the following procedure:

Aluminum isopropoxide (10- grams), 3-fluoro saligenin (2.84 grams) andtertiary butyl alcohol (500 cc.) were refluxed for three hours, andtertiary butyl alcohol (about 300 cc.) was then distilled, together withsubstantially all the isopropyl alcohol, from the resulting products.Acetone (500 grams) was added to the residue, and the mixture soproduced was refluxed gently for 20 hours, cooled, and filtered. Thefiltrate and sodium hydroxide (200 cc. of a 25 weight per cent aqueoussolution) were then added to a distilling flask. The solids filteredfrom the reaction mixture were treated with sulfuric acid (50 cc. of a10 weight per cent aqueous solution); when the aluminum complex haddissolved in the acid medium, the solution was made basic by theaddition of sodium hydroxide (about 20 cc. of a 25 weight per centaqeous solution) and the resulting basic solution was combined with thefiltrate and sodium hydroxide in the distilling flask. The entiremixture was heated until all alcohol, acetone, and other volatileorganic matter was distilled. The residue from the distillation was thenacidified with aqueous sulfuric acid and the desired products separatedfrom the other materials by a steam distillation. A. small amount of3-fluoro salicylaldehyde separated from the distillate of this steamdistillation. The distillate was treated with toluidine (3 grams) inacetic acid (25 cc. of a 20 weight per cent aqueous solution). TheSchiffs base so produced was separated by filtration and air dried. Theamount of Schiffs base recovered (-0.20 gram) indicated a 4.4 per centconversion of the 3- fiuoro saligenin to 3-fluoro salicylaldehyde.

Example 2 A procedure similar to that described in Example 1 was used'toproduce 3-fluoro salicylaldehyde except that o-chloro-benzylaldehyde wasused as the carbonyl containing compound. Aluminum isopropoxide (10grams), 3-fiuoro saligenin (2.84 grams) and tertiary butyl alcohol (500cc.) were refluxed for about sixteen hours. and volatile material wasthen distilled to concentrate the solution to cc. Tertiary butyl alcohol(300 cc.) and o-chlorobenzylaldehyde (300 cc.) were added to theconcentrate and the resulting mixture was refluxed gently for sixteenhours, cooled, and filtered. Sulfuric acid (200 cc. of a 10 weight percent aqueous solution) was added to the cooled mixture, and the reac--tion mixture was then made alkaline by gradual additions of sodiumhydroxide (a 50 weight per cent solution). The alkaline aqueous phasewas separated from the organic phase in a separatory funnel, and theorganic layer was then extracted twice more with 10 weight per centaqueous 'cated a 47 per. cent conversion of the 3-fiuor0 saligenin tothe corresponding-aldehyde.

Example-3 Aluminum :tertiary butoxide' was produced according to thefollowing procedure:

A mixture of aluminum turnings (64 grams), mercuric chloride (0.5 gram)and tertiary butyl alcohol (200 grams) was refluxed gently. Afterrefluxing for. one hour additional tertiary butyl alcohol (a total of150 grams) was added at such a rate that the exothermic reaction did notoverheat the mixture. Refluxing was continued for an additional sixteenhours.

An excess of the aluminum tertiary butoxide produced as described inthepreceding paragraph was mixed'with-5-chloro-3 fluoro saligenin grams)and o-chloro-benzylaldehyde (40 grams) was added. This mixture was heldat a temperature between C. and C. for ten hours; the solids inthe-flask were dissolved by adding 10 weight per cent aqueoussulfuricacid; this solution was then made alkaline and steam distilled; and theresidue was acidified and steam distilled to-produce two gramsof crude5-chloro-3-fiuoro salicylaldehyde.

Weclaim:

1. A method of producing an o-hydroxy aldehyde from a substituted phenolhaving (a) one ortho substituent of the formula CH2OH and (b) not more.than four other substituents each of whichis of the. class consisting ofhalo, alkyl and alkoxy, which method comprises (1) treating thesubstituted phenol with a lower alkoxide of aluminum to forman aluminumderivative of the. substituted phenol; (2) subjecting the aluminumderivative to the action of a carbonylcontaining organic compound toproduce an aluminum salt of. the o-hydroxy aldehyde; and (3) adjustingthe pH of the resulting mixture to convert the aluminum salt of thehydroxy aldehyde to the free hydroxy aldehyde.

2. A method of producing a halo-o-hydroxy saligenin (2); .subjectingthe,aluminum derivae tive to theaction-of acarbonyl-containing. organiccompound to, produce. an aluminum salt of the o-hydroxy; aldehyde, and(3) adjusting the pH of the resulting mixture to convert the aluminumsalt of the hydroxy aldehyde to the free hydroxy aldehyde.

3. A method-of producing a fiuoro-o-hydroxy aldehyde that comprises (1)treating a monofiuorosaligenin with tertiary-butyl aluminate to form analuminum -derivative-*- of the fluorosaligenin, (2) subjecting thealuminum derivative to the action of an aldehyde to produce an aluminumsalt of the o-hydroxy aldehyde, and (3) adjusting the.pH:ofithe1-resulting mixture. to convertthe aluminumsalt of the-hydroxyaldehyde to the free -hydroxy:aldehyde.

4...A method of producing 3-fluorosalicylaldehyde that comprises ('1)treating 3-fluorosaligenin with tertiary butyl. aluminate to form analuminum derivative of the fluorosaligenin, (2) subjecting the aluminumderivative to the action of an aromatic aldehydeto produce an aluminumsalt of the o-hydroxy aldehyde, (3) adjusting the pH of the resulting.mixture-to convert the aluminum salt of theghydroxy aldehyde to the freehydroxy aldehyde, and separating the 3-fiuorosalicylaldehyde.

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Davies'et al., J. Chem. Ind., vol. 62, p. 109 (1943). r

Adams, Organic Reactions, vol. II, page 181; 207, John Wiley & SonNewYork (1944).

Yamashita et al., J. Chem. Soc. Japan, vol. (54, p. 506 (1943).Abstracted Chem. Abstracts, vol. 41, p. 3753 (1947).

Baker et al., Jour. Am. Chem. 800., vol. '70, pages 2594 to 2595 (1948).

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Schinz'et al., Helv. Chim. Acta, vol. 31, p. 2235 (1948), vol. 6 (1951),John Wiley and Sons, New

York, p. 222-223.

1. A METHOD OF PRODUCING AN O-HYDROXY ALDEHYDE FROM A SUBSTITUTED PHENOLHAVING (A) ONE ORTHO SUBSTITUENT OF THE FORMULA -CH2OH AND (B) NOT MORETHAN FOUR OTHER SUBSTITUENTS EACH OF WHICH IS OF THE CLASS CONSISTING OFHALO, ALKYL AND ALKOXY, WHICH METHOD COMPRISES (1) TREATING THESUBSTITUTED PHENOL WITH A LOWER ALKOXIDE OF ALUMINUM TO FORM AN ALUMINUMDERIVATIVE OF THE SUBSTITUTED PHENOL; (2) SUBJECTING THE ALUMINUMDERIVATIVE TO THE ACTION OF A CARBONYLCONTAINING ORGANIC COMPOUND TOPRODUCE AN ALUMINUM SALT OF THE O-HYDROXY ALDEHYDE; AND (3) ADJUSTINGTHE PH OF THE RESULTING MIXTURE TO CONVERT THE ALUMINUM SALT OF THEHYDROXY ALDEHYDE TO THE FREE HYDROXY ALDEHYDE.